RÉSUMÉ
The discovery and development of CDK2 inhibitors has currently been validated as a hot topic in cancer therapy. Herein, a series of novel N-(pyridin-3-yl)pyrimidin-4-amine derivatives were designed and synthesized as potent CDK2 inhibitors. Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC50 values of 0.83, 2.12, 3.12, and 8.61 µM, respectively, which were comparable to that of Palbociclib and AZD5438. Interestingly, these compounds were less toxic on normal embryonic kidney cells HEK293 with high selectivity index. Further mechanistic studies indicated 7l caused cell cycle arrest and apoptosis on HeLa cells in a concentration-dependent manner. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC50 of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes.
Sujet(s)
Antinéoplasiques , Tumeurs , Humains , Kinase-2 cycline-dépendante , Relation structure-activité , Lignée cellulaire tumorale , Cellules HeLa , Amines/pharmacologie , Cellules HEK293 , Inhibiteurs de protéines kinases/pharmacologie , Antinéoplasiques/pharmacologie , Prolifération cellulaire , Structure moléculaire , Tests de criblage d'agents antitumoraux , Tumeurs/traitement médicamenteuxRÉSUMÉ
Following our previously reported compound 3, we designed and synthesized a series of new 2-(substituted amino)- [1,2,4]triazolo[1,5-a]pyrimidines as potential tubulin polymerization inhibitors. Among them, analogue 4k, having a 3-hydroxy-4-methoxyphenylamino group, was observed to display excellent antiproliferative activity toward HeLa, HCT116, A549, and T47D with the IC50 values of 0.31, 1.28, 3.99 and 10.32 µM, respectively, which were approximately 32, 48, 4, and 5-fold improvement compared with 3. Importantly, 4k possessed significant selectivity in inhibiting cancer cell lines over the normal HEK293 cells. Moreover, futher mechanism analysis demonstrated that 4k caused G2/M arrest, induced cells apoptosis in HeLa cells, and manifested significant tubulin polymerization inhibitory activity with the IC50 value of 4.9 µM, which is comparable to CA-4 (IC50 = 4.2 µM). The observations performed in this study reveal that 2-arylamino- [1,2,4]triazolo[1,5-a]pyrimidines represent a novel class of tubulin polymerization inhibitors with potent antiproliferative efficacy.
Sujet(s)
Antinéoplasiques , Modulateurs de la polymérisation de la tubuline , Humains , Modulateurs de la polymérisation de la tubuline/pharmacologie , Pyrimidines/pharmacologie , Tests de criblage d'agents antitumoraux , Apoptose , Cellules HeLa , Cellules HEK293 , Conception de médicament , Relation structure-activité , Lignée cellulaire tumorale , Antinéoplasiques/pharmacologie , Structure moléculaire , Prolifération cellulaire , Points de contrôle de la phase G2 du cycle cellulaire , Tubuline/métabolisme , PolymérisationRÉSUMÉ
Based on our previous work, a series of novel 6-arylamino-[1,2,4]triazolo[4,3-a]pyridine derivatives were synthesized, and evaluated for antiproliferative activities. SAR studies revealed that inserting an amino linkage between 6aryl group and [1,2,4]triazolo[4,3-a]pyridine core led to amuch broaderantitumorspectrum, and the most promising compound 8 l exerted potent andbroad-spectrum antiproliferative activity toward HeLa, HCT116, MCF-7, and A549 cell lines, with IC50 values in the micromolar range of 5.98-12.58 µM, which were more active than the positive control 5-FU. The mechanism investigation illustrated that 8 l dose-dependently caused cell cycle arrest at the G2/M phase, and induced cell apoptosis in HeLa cells. Consequently, these findings suggest the 6-arylamino-[1,2,4]triazolo[4,3-a]pyridines afford significant potential for the discovery of a new highly efficient anticancer agents.
Sujet(s)
Antinéoplasiques , Triazoles , Antinéoplasiques/pharmacologie , Prolifération cellulaire , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Fluorouracil/pharmacologie , Cellules HeLa , Humains , Structure moléculaire , Pyridines/pharmacologie , Relation structure-activité , Triazoles/pharmacologieRÉSUMÉ
Based on our previous work, a series of novel triazolylthioacetones incorporating pyridine, pyrazine, and 3,4,5-trimethoxybenzyl fragment were synthesized, and evaluated for antiproliferative activities and interactions with tubulin. Some analogues exhibited moderate to excellent potency, with the most promising compound IIc possessing IC50 values of 0.62, 1.46, and 3.65 µM against HT-29, HCT116, and HepG2 tumor cells, respectively, which were comparable with the positive control CA-4. Mechanistical studies revealed that IIc concentration-dependently caused cell cycle arrest at the G2/M phase in HCT116 tumor cells, and displayed a significant inhibition of tubulin polymerization with an IC50 value of 12.7 µM. Moreover, molecular docking analysis suggested that IIc could occupy the colchicine-binding site in a similar way with typical tubulinpolymerizationinhibitors. These results highlighted the 4-amino-triazolylthioacetone scaffold as potential tubulin polymerization inhibitors for development of highly efficient anticancer agents.
Sujet(s)
Antinéoplasiques , Tubuline , Antinéoplasiques/composition chimique , Lignée cellulaire tumorale , Prolifération cellulaire , Tests de criblage d'agents antitumoraux , Humains , Simulation de docking moléculaire , Structure moléculaire , Pyrazines/pharmacologie , Pyridines/pharmacologie , Relation structure-activité , Tubuline/métabolisme , Modulateurs de la polymérisation de la tubuline/composition chimiqueRÉSUMÉ
CDK4/6 have been validated as the cancer therapeutic targets. Here, we describe a series of pteridin-7(8H)-one analogues as potent CDK4/6 inhibitors. Among them, the most promising compound 7s demonstrated remarkable and broad-spectrum antiproliferative activities toward HCT116, HeLa, MDA-MB-231, and HT-29 cells with IC50 values of 0.65, 0.70, 0.39, and 2.53 µM, respectively, which were more potent than that of the anticancer drug Palbociclib. Interestingly, 7s also manifested the greatest inhibitory activities toward both CDK4/cyclin D3 and CDK6/cyclin D3 (IC50 = 34.0 and 65.1 nM, respectively), which was comparable with Palbociclib. Additionally, molecular simulation indicated that 7s bound efficiently at the ATPbindingsitesofCDK4 and CDK6. Further mechanistic studies revealed that compound 7s could concentration-dependently induce cell cycle arrest and apoptosis in HeLa cells. Takentogether, 7s represents a promising novel CDK4/6 inhibitor for the potential treatment of cancer.
Sujet(s)
Antinéoplasiques/pharmacologie , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Développement de médicament , Inhibiteurs de protéines kinases/pharmacologie , Ptéridines/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Apoptose/effets des médicaments et des substances chimiques , Cycle cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Kinase-4 cycline-dépendante/métabolisme , Kinase-6 cycline-dépendante/métabolisme , Relation dose-effet des médicaments , Humains , Simulation de docking moléculaire , Structure moléculaire , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/composition chimique , Ptéridines/synthèse chimique , Ptéridines/composition chimique , Relation structure-activitéRÉSUMÉ
In order to discover new anticancer agents, 25 novel 2,4-diamino-5-methyleneaminopyrimidine derivatives were designed and synthesized based on our previous work via a ring-opening strategy. Among them, compared with 5-FU, compound 7i exhibited 4.9-, 2.9-, 2.1-, and 3.0-fold improvement in inhibiting HCT116, HT-29, MCF-7, and HeLa cells proliferation with IC50 values of 4.93, 5.57, 8.84, and 14.16 µM, respectively. Moreover, further mechanistic studies indicated that compound 7i could concentration-dependently induce cell cycle arrest and apoptosis in HCT116 cells. These findings revealed that 2,4-diamino-5-methyleneaminopyrimidine scaffold has potential for further investigation to explore novel anticancer agents.
Sujet(s)
Antinéoplasiques/pharmacologie , Conception de médicament , Pyrimidines/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Apoptose/effets des médicaments et des substances chimiques , Points de contrôle du cycle cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Humains , Structure moléculaire , Pyrimidines/synthèse chimique , Pyrimidines/composition chimique , Relation structure-activitéRÉSUMÉ
By removing 5-methyl and 6-acetyl groups in our previously reported compound 3, we designed a series of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine derivatives as potential tubulin polymerization inhibitors. Among them, compound 5e displayed low nanomolar antiproliferative efficacy on HeLa cells which was 166-fold higher than the lead analogue 3. Interestingly, 5e displayed significant selectivity in inhibiting cancer cells over HEK-293 (normal human embryonic kidney cells). In addition, 5e dose-dependently arrested HeLa in G2/M phase through the alterations of the expression levels of p-cdc2 and cyclin B1, and caused HeLa cells apoptosis by regulation of expressions of cleaved PARP. Further evidence demonstrated that 5e effectively inhibited tubulin polymerization and was 3-fold more powerful than positive control CA-4. Moreover, molecular docking analysis indicated that 5e overlapped well with CA-4 in the colchicine-binding site. These studies demonstrated that 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine skeleton might be used as the leading unit to develop novel tubulin polymerization inhibitors as potential anticancer agents.
Sujet(s)
Antinéoplasiques/pharmacologie , Découverte de médicament , Pyrimidines/pharmacologie , Modulateurs de la polymérisation de la tubuline/pharmacologie , Tubuline/métabolisme , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Apoptose/effets des médicaments et des substances chimiques , Lignée cellulaire , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Humains , Simulation de docking moléculaire , Structure moléculaire , Polymérisation/effets des médicaments et des substances chimiques , Pyrimidines/synthèse chimique , Pyrimidines/composition chimique , Relation structure-activité , Modulateurs de la polymérisation de la tubuline/synthèse chimique , Modulateurs de la polymérisation de la tubuline/composition chimiqueRÉSUMÉ
Based on our previous research, thirty new 5-amino-1H-1,2,4-triazoles possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities. Among them, compounds IIa, IIIh, and IIIm demonstrated significant antiproliferative activities against a panel of tumor cell lines, and the promising compound IIIm dose-dependently caused G2/M phase arrest in HeLa cells. Furthermore, analogue IIa exhibited the most potent tubulinpolymerization inhibitory activity with an IC50 value of 9.4 µM, and molecular modeling studies revealed that IIa formed stable interactions in the colchicine-binding site of tubulin, suggesting that 5-amino-1H-1,2,4-triazole scaffold has potential for further investigation to develop novel tubulin polymerization inhibitors with anticancer activity.
Sujet(s)
Antinéoplasiques/pharmacologie , Triazoles/pharmacologie , Modulateurs de la polymérisation de la tubuline/pharmacologie , Tubuline/métabolisme , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Points de contrôle du cycle cellulaire/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Cellules HeLa , Humains , Structure moléculaire , Polymérisation/effets des médicaments et des substances chimiques , Relation structure-activité , Triazoles/synthèse chimique , Triazoles/composition chimique , Modulateurs de la polymérisation de la tubuline/synthèse chimique , Modulateurs de la polymérisation de la tubuline/composition chimiqueRÉSUMÉ
Based on our previous work, a novel class of 8-cyclopentyl-7,8-dihydropteridin-6(5H)-one derivatives were synthesized and evaluated as antiproliferative agents. Structure-activity relationship analysis revealed that the greatest activities were achieved with a 4-(4-methylpiperazin-1-yl)aniline group at C-2 position of dihydropteridin-6(5H)-one core, and the most promising compound 6k demonstrated comparable antiproliferative activity with Palbociclib and more potent than our parent derivative 4 toward four cell lines including HCT-116, HeLa, HT-29, and MDA-MB-231 with IC50 values of 3.29, 6.75, 7.56, and 10.30 µM, respectively. Moreover, the mechanism studies revealed that compound 6k could induce cell cycle arrest at G2/M phase via a concentration-dependent manner. In general, these preliminary observations suggested that these compounds could serve as promising scaffolds for further modification to develop novel and highly potent cancer therapy agents.
Sujet(s)
Antinéoplasiques/pharmacologie , Ptéridines/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Humains , Structure moléculaire , Ptéridines/synthèse chimique , Ptéridines/composition chimique , Relation structure-activitéRÉSUMÉ
A new series of derivatives characterized by the presence of the 3,4,5-trimethoxylbenzamide substituted benzofurans were synthesized and evaluated for antiproliferative activity against four cancer cell lines and one normal human cell line. Among them, derivative 6g with greatest cytotoxicity significantly inhibited the growth of MDA-MB-231, HCT-116, HT-29 and HeLa cell lines with IC50 values of 3.01, 5.20, 9.13, and 11.09 µM, respectively. Importantly, 6g possessed excellent selectivity over non-tumoral cell lines HEK-293 (IC50 > 30 µM). Moreover, mechanistic studies revealed that 6g induced HeLa cells arrested in G2/M phase in a concentration-dependent manner, and inhibited polymerization of tubulin via a consistent way with CA-4. In general, these observations suggest that 6g is a promising anti-cancer lead and is worth further investigation to generate potential antitumor agents.
Sujet(s)
Benzamides/synthèse chimique , Benzamides/usage thérapeutique , Polymérisation/effets des médicaments et des substances chimiques , Modulateurs de la polymérisation de la tubuline/usage thérapeutique , Tubuline/composition chimique , Benzamides/pharmacologie , Conception de médicament , Cellules HeLa , Humains , Structure moléculaire , Relation structure-activité , Modulateurs de la polymérisation de la tubuline/pharmacologieRÉSUMÉ
On the basis of our previous work, twenty-nine novel [1,2,4]triazolo[4,3-a]pyridines possessing 3,4,5-trimethoxylphenyl groups were designed, synthesized, and evaluated as tubulin polymerization inhibitors. The bioassay results revealed that some of the compounds displayed excellent antiproliferative efficacies in the nanomolar range against HeLa cells, and the most promising derivative 7i demonstrated almost comparable activity to that of the reference CA-4 and sixty-two fold more potent than the parent compound 6 with an IC50 value of 12 nM. Importantly, 7i exhibited high selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 µM). Further mechanism studies revealed that 7i significantly arrested cell cycle at G2/M phase, induced apoptosis with a dose-dependent manner, and disrupted microtubule networks. Additionally, the most active compound 7i effectively inhibited tubulin polymerization with a value similar to that of CA-4 (3.4 and 4.2 µM, respectively). Furthermore, molecular docking analysis suggested that 7i well occupied the colchicine binding pocket of tubulin. The present study highlights that compound 7i is a novel potential tubulin polymerization inhibitor and deserves further investigation for the treatment of cancers.
Sujet(s)
Pyridines/composition chimique , Triazoles/composition chimique , Modulateurs de la polymérisation de la tubuline/synthèse chimique , Modulateurs de la polymérisation de la tubuline/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Cycle cellulaire/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Cellules HEK293 , Cellules HeLa , Humains , Concentration inhibitrice 50 , Analyse spectrale/méthodesRÉSUMÉ
Twenty-six novel pyrazolo[3,4-b]pyridine-bridged analogues of combretastatin A-4 possessing 3,4,5-trimethoxylphenyl groups, were synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. Preliminary biological evaluation demonstrated that some of the target compounds displayed significant antiproliferative effectagainst four different cell lines including MCF-7, MDA-MB-231, HeLa and Kyse150. The most active analogue 6n was found to induce HeLa cells arrest in the G2/M phase in a dose-dependent manner. Molecular modeling studies indicated that derivative 6n most likely occupies the colchicine site of tubulin. The initial results suggest that the 3,4,5-trimethoxyphenyl substituted pyrazolo[3,4-b]pyridine could serve as a promising scaffold for development of potent tubulin inhibitors as anticancer agents.
Sujet(s)
Antinéoplasiques/pharmacologie , Pyrazoles/pharmacologie , Pyridines/pharmacologie , Stilbènes/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Humains , Modèles moléculaires , Structure moléculaire , Pyrazoles/synthèse chimique , Pyrazoles/composition chimique , Pyridines/synthèse chimique , Pyridines/composition chimique , Stilbènes/composition chimique , Relation structure-activitéRÉSUMÉ
As restricted CA-4 analogues, a novel series of [1,2,4]triazolo[1,5-a]pyrimidines possessing 3,4,5-trimethoxylphenyl groups has been achieved successfully via an efficient one-pot three-component reaction of 3-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-5-amine, 1,3-dicarbonyl compounds and aldehydes. Initial biological evaluation demonstrated some of target compounds displayed potent antitumor activity in vitro against three cancer cell lines. Among them, the most highly active analogue 26 inhibited the growth of HeLa, and A549 cell lines with IC50 values at 0.75, and 1.02⯵M, respectively, indicating excellent selectivity over non-tumoural cell line HEK-293 (IC50â¯=â¯29.94⯵M) which suggested that the target compounds might possess a high safety index. Moreover, cell cycle analysis illustrated that the analogue 26 significantly induced HeLa cells arrest in G2/M phase, meanwhile the compound could dramatically affect cell morphology and microtubule networks. In addition, compound 28 exhibited potent anti-tubulin activity with IC50 values of 9.90⯵M, and molecular docking studies revealed the analogue occupied the colchicine-binding site of tubulin. These observations suggest that [1,2,4]triazolo[1,5-a]pyrimidines represent a new class of tubulin polymerization inhibitors and well worth further investigation aiming to generate potential anticancer agents.
Sujet(s)
Antinéoplasiques/pharmacologie , Conception de médicament , Pyrimidines/pharmacologie , Triazoles/pharmacologie , Modulateurs de la polymérisation de la tubuline/pharmacologie , Tubuline/métabolisme , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Cellules HEK293 , Humains , Structure moléculaire , Pyrimidines/synthèse chimique , Pyrimidines/composition chimique , Relation structure-activité , Triazoles/synthèse chimique , Triazoles/composition chimique , Modulateurs de la polymérisation de la tubuline/synthèse chimique , Modulateurs de la polymérisation de la tubuline/composition chimique , Cellules cancéreuses en cultureRÉSUMÉ
To develop novel CDK2 inhibitors as anticancer agents, a series of novel pyrimidine-based benzothiazole derivatives were designed and synthesized. Initial biological evaluation demonstrated some of target compounds displayed potent antitumor activity in vitro against five cancer cell lines. Especially, the analogue 10s exhibited approximately potency with AZD5438 toward four cells including HeLa, HCT116, PC-3, and MDA-MB-231 with IC50 values of 0.45, 0.70, 0.92, 1.80⯵M, respectively. More interestingly, the most highly active compound 10s in this study also possessed promising CDK2/cyclin A2 inhibitory activities with IC50 values of 15.4â¯nM, which was almost 3-fold potent than positive control AZD5438, and molecular docking studies revealed that the analogue bound efficiently with the CDK2 binding site. Further studies indicated that compound 10s could induce cell cycle arrest and apoptosis in a concentration-dependent manner. These observations suggest that pyrimidine-benzothiazole hybrids represent a new class of CDK2 inhibitors and well worth further investigation aiming to generate potential anticancer agents.
Sujet(s)
Antinéoplasiques/pharmacologie , Benzothiazoles/pharmacologie , Kinase-2 cycline-dépendante/antagonistes et inhibiteurs , Découverte de médicament , Inhibiteurs de protéines kinases/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Apoptose/effets des médicaments et des substances chimiques , Benzothiazoles/synthèse chimique , Benzothiazoles/composition chimique , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Kinase-2 cycline-dépendante/métabolisme , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Humains , Structure moléculaire , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/composition chimique , Relation structure-activitéRÉSUMÉ
A highly efficient method has been developed for the one-pot synthesis of substituted 3-amino-1H-indole and 3-amino-1H-7-azaindole derivatives starting from ethyl 2-cyanophenylcarbamate/ethyl 3-cyanopyridin-2-ylcarbamate, and α-bromoketones in good to excellent yields. All newly synthesized analogues were screened for their antiproliferative activities against four cancer cell lines. The most promising compound 8v demonstrated 13-, 5-, and 1.4-fold improvement compared to fluorouracil in inhibiting HeLa, HepG2, and MCF-7 cell proliferation with IC50 values of 3.7, 8.0, and 19.9⯵M, respectively. Furthermore, 8v induced significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. These encouraging findings indicate that the common 3-amino-1H-7-azaindole is a very favorable scaffold for the design of novel anticancer small-molecule drugs.
Sujet(s)
Antinéoplasiques/pharmacologie , Composés aza/pharmacologie , Indoles/pharmacologie , Antinéoplasiques/synthèse chimique , Apoptose/effets des médicaments et des substances chimiques , Composés aza/synthèse chimique , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Tests de criblage d'agents antitumoraux , Points de contrôle de la phase G2 du cycle cellulaire/effets des médicaments et des substances chimiques , Humains , Indoles/synthèse chimique , Structure moléculaire , Relation structure-activitéRÉSUMÉ
A series of novel 3-amidoindole derivatives possessing 3,4,5-trimethoxylphenyl groups were synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. Some of them demonstrated moderate to potent activities in vitro against six cancer cell lines including MCF-7, MDA-MB-231, BT549, T47D, MDA-MB-468, and HS578T. The most active compound 27 inhibited the growth of T47D, BT549, and MDA-MB-231â¯cell lines with IC50 values at 0.04, 3.17, and 6.43⯵M, respectively. Moreover, the flow cytometric analysis clearly revealed that compound 27 significantly inhibited growth of breast cancer cells through arresting cell cycle in G2/M phase via a concentration-dependent manner. In addition, the compound also exhibited the most potent anti-tubulin activity with IC50 values of 9.5⯵M, which was remarkable, compared to CA-4. Furthermore, molecular docking analysis demonstrated the interaction of the compound 27â¯at the colchicine-binding site of tubulin. These preliminary results suggest that compound 27 is a very promising tubulin-binding agent and is worthy of further investigation aiming to the development of new potential anticancer agents.
Sujet(s)
Tubuline/effets des médicaments et des substances chimiques , Sites de fixation , Points de contrôle du cycle cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Colchicine/métabolisme , Tests de criblage d'agents antitumoraux , Humains , Indoles/synthèse chimique , Indoles/métabolisme , Indoles/pharmacologie , Concentration inhibitrice 50 , Simulation de docking moléculaire , Polymérisation/effets des médicaments et des substances chimiques , Relation structure-activité , Tubuline/métabolismeRÉSUMÉ
Based on our previous work, a series of novel 2-amino-7,8-dihydropteridin-6(5H)-one derivatives were designed and synthesized via a ring-closing strategy. Biological evaluation with four human cancer cell lines (BT549, T47D, MDA-MB-468, and MDA-MB-231) showed that most of these compounds possessed moderate to potent antiproliferative activities. The most promising compound 8-benzyl-2-(phenethylamino)-7,8-dihydropteridin-6(5H)-one (6q) possessing IC50 values of 7.75, 6.37, and 10.73µM against MDA-MB-468, T47D, and BT549, respectively, which were 49, 11, and 8 folds more active than the positive control fluorouracil. Moreover, fluorescence-activated cell sorting analysis revealed that compound 6q displayed a significant effect on G1 cell-cycle arrest in a concentration-dependent manner in T47D cells. The initial structure-activity relationship studies indicated that linker-length of amine chain in C-2 position of pyrimidine ring played a crucial role in modulating the antitumor activity, which could be of help in the rational design of dihydropteridin-6(5H)-ones as novel anticancer drugs.
Sujet(s)
Antinéoplasiques/pharmacologie , Conception de médicament , Ptéridines/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Humains , Structure moléculaire , Ptéridines/synthèse chimique , Ptéridines/composition chimique , Relation structure-activitéRÉSUMÉ
Based on our previous screening hit compound 1, a series of novel indole-pyrimidine hybrids possessing morpholine or thiomorpholine moiety were synthesized via an efficient one-pot multistep synthetic method. The antiproliferative activities of the synthesized compounds were evaluated in vitro against four cancer cell lines including HeLa, MDA-MB-231, MCF-7, and HCT116. The results revealed that most compounds possessed moderate to excellent potency. The IC50 values of the most promising compound 15 are 0.29, 4.04, and 9.48 µM against MCF-7, HeLa, and HCT116 cell lines, respectively, which are 48.0, 4.9, and 1.8 folds more active than the lead compound 1. Moreover, fluorescence-activated cell sorting analysis revealed that compound 14 showing the highest activity against HeLa (IC50 = 2.51 µM) displayed a significant effect on G2/M cell-cycle arrest in a concentration-dependent manner in HeLa cell line. In addition, representative nine active hybrids were evaluated for tubulin polymerization inhibitory activities, and compound 15 exhibited the most potent anti-tubulin activity showing 42% inhibition at 10 µM. These preliminary results encourage a further investigation on indole-pyrimidine hybrids for the development of potent anticancer agents that inhibit tubulin polymerization.
Sujet(s)
Antinéoplasiques/pharmacologie , Indoles/pharmacologie , Morpholines/pharmacologie , Pyrimidines/pharmacologie , Modulateurs de la polymérisation de la tubuline/pharmacologie , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Points de contrôle du cycle cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Conception de médicament , Tests de criblage d'agents antitumoraux , Humains , Indoles/synthèse chimique , Indoles/composition chimique , Simulation de docking moléculaire , Morpholines/synthèse chimique , Morpholines/composition chimique , Tumeurs/traitement médicamenteux , Tumeurs/métabolisme , Pyrimidines/synthèse chimique , Pyrimidines/composition chimique , Relation structure-activité , Tubuline/métabolisme , Modulateurs de la polymérisation de la tubuline/synthèse chimique , Modulateurs de la polymérisation de la tubuline/composition chimiqueRÉSUMÉ
Thirty-two novel 3-alkylsulfanyl-1,2,4-triazole derivatives, designed as cis-restricted combretastatin A-4 analogues, were synthesized and evaluated for their antiproliferative activities. The results indicated that analogue 20 showed more potent antiproliferative activities against PC-3 cell lines than positive control CA-4. Particularly, the most promising compound 25 displayed 5-fold improvement compared to CA-4 in inhibiting HCT116 cell proliferation with IC50 values of 1.15 µM. Further flow-activated cell sorting analysis revealed that compound 20 displayed a significant effect on G2/M cell-cycle arrest in a dose-dependent manner in PC-3 cells. From this study, analogues 20 and 25 were the most potent anti-cancer agents in this structural class, and were considered lead compounds for further development as anti-cancer drugs.
Sujet(s)
Antinéoplasiques/composition chimique , Antinéoplasiques/pharmacologie , Bibenzyles/composition chimique , Bibenzyles/pharmacologie , Triazoles/composition chimique , Triazoles/pharmacologie , Points de contrôle du cycle cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Tests de criblage d'agents antitumoraux , Humains , Tumeurs/traitement médicamenteux , Tumeurs/métabolisme , Stéréoisomérie , Relation structure-activitéRÉSUMÉ
Based on our previous work, a series of novel 3-alkylsulfanyl-4-amino-1,2,4-triazole derivatives were designed, synthesized and evaluated for their antiproliferative activities. The results indicated that some compounds possessed significant antiproliferative activities against four cancer cell lines, HepG2, HCT116, PC-3, and Hela. Particularly, the most promising compound 8d displayed 184-, 18-, and 17-fold improvement compared to fluorouracil in inhibiting HCT116, Hela and PC-3 cell proliferation with IC50 values of 0.37, 2.94, and 31.31µM, respectively. Most interestingly, the compound did not affect the normal human embryonic kidney cells, HEK-293. Moreover, mechanistic investigation showed that the representative compound 8d induced apoptosis and blocked cell cycle in G2/M phase in Hela cells in a dose-dependent manner. These findings suggest that compound 8d may have potential to be developed as a promising lead for the design of novel anticancer small-molecule drugs.